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Hepatitis C and double-hit B cell lymphoma successfully treated by antiviral therapy

Hepatitis C and double-hit B cell lymphoma successfully treated by antiviral therapy Author contributions: All the authors contributed equally to the conception and design of the article. B cells lymphoma is one of the most challenging extra- hepatic manifestations of hepatitis C virus (HCV). Institutional review board statement: This case report Recently, a new kind of B-cell lymphoma, named double- was exempt from the Institutional Review Board standards at hit B (DHL), was characterized with an aggressive University of Campus Bio Medico of Rome. clinical course whereas a potential association with HCV was not investigated. The new antiviral direct agents Informed consent statement: The patient involved in this clinical case gave her written informed consent authorizing use (DAAs) against HCV are effective and curative in the and disclosure of her protected health information. majority of HCV infections. We report the first case, to our knowledge, of DHL and HCV-infection successfully Conflict-of-interest statement: All the authors have no treated by new DAAs. According to our experience, a DHL conflicts of interests to declare. must be suspected in case of HCV-related lymphoma, and an early diagnosis could direct towards a different Open-Access: This article is an open-access article which was hematological management because a worse prognosis selected by an in-house editor and fully peer-reviewed by external might be expected. A possible effect of DAAs on DHL reviewers. It is distributed in accordance with the Creative regression should be investigated, but eradicating HCV Commons Attribution Non Commercial (CC BY-NC 4.0) license, would avoid life-threatening reactivation of viral hepatitis which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on during pharmacological immunosuppression in onco- different terms, provided the original work is properly cited and haematological diseases. the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ Key words: Hepatitis C; Lymphoma; Direct antiviral agents; Double hit lymphoma; Chronic hepatitis C Manuscript source: Unsolicited manuscript © The Author(s) 2016. Published by Baishideng Publishing Correspondence to: Giovanni Galati, MD, Unit of Internal Group Inc. All rights reserved. Medicine and Hepatology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Core tip: Rome, Italy. g.galati@unicampus.it B cells lymphoma is one of the most chall- WJH|www.wjgnet.com 1244 October 18, 2016|Volume 8|Issue 29| Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma enging extra-hepatic manifestations of hepatitis C other risk factors for hepatitis virus transmission. The virus. Recently, a new kind of B-cell lymphoma, named CHC was sustained by genotype 1b virus, with low necro- Double-hit B, was characterized with an aggressive inflammatory activity and mild liver fibrosis according clinical course. This is the first case described in literature to non-invasive evaluation performed by Fibroscan of double hit lymphoma with co-existing chronic (4.5 kPa), whereas HCV showed a high replication rate hepatitis C, successfully treated by new direct antiviral (4500000 UI/mL, Cobas AmpliPrep/Cobas TaqMan -Roche, therapies. This case suggests a potential favorable Rotkreuz, Switzerland). Ultrasound scans of the liver did effect of the new antiviral therapies on double hit not demonstrate signs of b fi rosis or spleen enlargement lymphoma regression. secondary to portal hypertension. Of interest, the patient reported a previous episode of major depression occurred in 2006 and, since then, she had been taking venlafazine Galati G, Rampa L, Vespasiani-Gentilucci U, Marino M, Pisani 75 mg/d. F, Cota C, Guidi A, Picardi A. Hepatitis C and double-hit B cell In July 2013, due to the enlargement of neck lymph lymphoma successfully treated by antiviral therapy. World J nodes, the patient underwent a hematological evaluation Hepatol 2016; 8(29): 1244-1250 Available from: URL: http:// and a lymph node biopsy, and she was n fi ally diagnosed www.wjgnet.com/1948-5182/full/v8/i29/1244.htm DOI: http:// with DLBCL (CD20+, CD30-, Bcl2+, Ki67 50%, Bcl6 + dx.doi.org/10.4254/wjh.v8.i29.1244 25%, negativity for CD10 and Mum1), with involvement of nodes on both sides of the diaphragm, bone marrow and spleen (Figure 1). Treatment with cyclophosphamide, doxorubicin, vincristine, prednisolone plus Rituximab INTRODUCTION (R) (R-CHOP regimen) plus prophylactic intrathecal Hepatitis C virus (HCV) is a major global public health injection of methotrexate and prednisone, was started. problem, although the newest and most effective In December 2013, i.e., after six courses of R-CHOP, antiviral therapies (AVTs), free from severe side effects the patient showed a complete remission of lymphoma related to interferon (IFN), are spreading in developed according both to Contrast Tomography plus Positron countries. This could lead in the next future to a lower Emission Tomography scans and to bone marrow biopsy. prevalence of chronic hepatitis C (CHC) and of its extra- Two additional doses of R were prescribed and, at that hepatic manifestations. Among these, the hematologic time, blood tests showed normal levels of transaminases, manifestations are the most challenging. Indeed, while HCV replication did not show any substantial HCV could induce B cell proliferation and cause mixed changes (Figure 2). In the following months, the patient [1] cryoglobulinaemia and non-Hodgkin lymphoma (NHL) . was referred to our Liver Unit and she was evaluated The typical HCV-related lymphomas are marginal zone for AVT. However, since “all-oral” AVTs for CHC was at lymphoma (MZL) and diffuse large B cell lymphoma that time unavailable in Italy, the patient was evaluated [2] (DLBCL) . The r fi st could benetfi from AVTs, whereas the for IFN-based AVT, but she presented relative and second group needs more aggressive chemotherapies absolute contraindications to IFN use, such as a previous and the only AVTs seem to be ineffective. More recently, episode of major depression, mild anemia, leucopenia a new kind of lymphoma named double-hit B cell (i.e., Haemoglobin 10.7 g/dL, White cells counts 1.980 (DHL) was described, characterized by chromosomal cells/mm ), as well as to ribavirin (RBV) use (anemia). rearrangements, specic fi ally of Myc oncogene and either We therefore asked our case to be evaluated for the B cell lymphoma 2 and B cell lymphoma 6 oncogenes expanded access program (EAP) which was ongoing [3,4] (Bcl2-Bcl6) or gene for Cyclin D1 (Ccnd1) . DHL with Paritaprevir (PTV), a NS3/4A protease inhibitor co- represents about 5% of all cases of DLBCL and affected formulated with NS5A inhibitor Ombitasvir (OBV) and patients generally have an aggressive clinical course the pharmacokinetic enhancer ritonavir (r), plus non- with poor prognosis, despite combination chemotherapy, nucleoside polymerase inhibitor Dasabuvir (DSV). Since with a median overall survival of less than 1-2 years. To lymphoma is a possible extra-hepatic manifestation of date, due to the limited literature concerning this type HCV, the pharmaceutical industry committee accepted of lymphoma, the specic fi treatment is still not clear. A our patient for participation to the EAP. Unfortunately, in potential correlation between HCV and DHL has never October 2014, the patient experienced the r fi st relapse of been investigated. lymphoma at the right maxillary sinus (Figure 3), whereas We describe the first case, to our knowledge, of a bilateral bone biopsies were negative. Since chemotherapy patient affected by DHL and CHC who underwent a was urgent, cisplatin, cytarabin, dexamethasone plus R successful antiviral treatment with IFN-free therapy (R-DHAP regimen) were started. After the second cycle (ombitasvir/paritaprevir/ritonavir and dasabuvir). of R-DHAP, liver tests worsened, with a rapid evolution to liver failure, i.e., jaundice and ascites (Figure 2). She was admitted to our Unit and the liver decompensation CASE REPORT was successfully treated with diuretics and anti-oxidant The patient was a 39-year-old Caucasian woman, who infusion (glutathione 2 g/d until recovery). tested HCV positive in 2013 during a routine medical From February 2015 to March 2015 she underwent evaluation. She had not history of blood transfusions or local radiotherapy on the right maxillary sinus (30 Gray). WJH|www.wjgnet.com 1245 October 18, 2016|Volume 8|Issue 29| Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma A B C H and E 200 × H and E 400 × CD20 400 × D E F Ki67 400 × Bcl6 400 × Mum1 400 × Figure 1 Histological and immunohistochemical features of the diffuse large B cell lymphoma at the primary diagnosis. A: In the lymph node a polymorphic lymphoid population is seen; B: Large lymphoid cells prevailed; C: These large cells were B CD20+; D: The proliferation rate marked by Ki67 was around 20% with respect to the overall population, but about 40% if compared with the blastic B cell population; E: The large B cells expressed mainly the germinal center marker Bcl6; F: Mum1 was not found expressed at the primary diagnosis. DLBCL: Diffuse large B cell lymphoma; H and E: Hematoxylin and eosin; CD: Clusters of differentiation; Ki67: Cellular marker for proliferation; Bcl6: B cell lymphoma 6; Mum1: Multiple myeloma oncogene 1. Liver Second First failure relapse relapse Diagnosis R-IEV R-CHOP R-DHAP R-IEVR RT R R R R Antiviral therapy 1 0 HCV-RNA (UI/mL) ALT (U/L) GGT (U/L) Figure 2 This figure shows the trends of gamma-glutamyl transpeptidase, alanine amino-transferase and hepatitis C viremia - RNA during chemo- therapies and antiviral therapy. R: Rituximab; R-CHOP: Cyclophosphamide, doxorubicin, vincristine, prednisolone plus Rituximab; R-DHAP: Cisplatin, cytarabin, dexamethasone plus Rituximab; R-IEV: Ifosfamide, etoposide, epirubicin plus Rituximab; GGT: Gamma-glutamyl transpeptidase; ALT: Alanine amino-transferase; HCV: Hepatitis C viremia. After the liver tests returned to normal levels, she started 12 wk (Figure 2). The HCV-RNA showed a fast drop the triple DAAs regimen in the EAP, for a duration of since after two weeks of AVT (42 UI/mL), while viremia WJH|www.wjgnet.com 1246 October 18, 2016|Volume 8|Issue 29| August 2013 November 2013 February 2014 May 2014 August 2014 November 2014 February 2015 May 2015 August 2015 Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma A B C H and E 200 × CD20 400 × H and E 400 × E F Bcl6 400 × Mum1 400 × Ki67 400 × Figure 3 Histological and immunohistochemical features of the diffuse large B cell lymphoma at the first relapse (mucosal). A: In the mucosal relapse a polymorphic lymphoid population was found; B: The rate of large lymphoid cells increased up to 80%; C: These large cells were B CD20+; D: The proliferation rate marked by Ki67 was around 50%-60% with respect to the blastic B cell population; E: The large B cells expressed the germinal center marker Bcl6 (about 50%-60%); F: Mum1 was found to be expressed now by about 70% of the cells. DLBCL: Diffuse large B cell lymphoma; H and E: Hematoxylin and eosin; CD: Clusters of differentiation; Ki67: Cellular marker for proliferation; Bcl6: B Cell lymphoma 6; Mum1: Multiple myeloma oncogene 1. became undetectable (limit of quantic fi ation according to subsequently, she underwent a second cycle of R/IEV/R our virological test was 15 UI/mL) after 8 wk of therapy, (regimen with an additive administration of R), which and persisted undetectable both at the end of AVT and was burdened by infective complications requiring hos- 24 wk after. However, in May 2015, i.e., after 4 wk from pitalization and prolonged antibiotic therapies. At the the end of AVT, the patient experienced a new relapse of last hepatological follow-up visit in November 2015, i.e., lymphoma (Figure 4). Due to the appearance of multiple 24 wk after the end of AVT, HCV-RNA was permanently cutaneous nodules on the middle third of the left arm, undetectable despite the immunosuppressive therapy. on the posterior region of the chest wall and on the right Afterwards, the patient was evaluated for an allogenic and left a fl nks, a biopsy of one of them was indicated, stem cells transplantation, which was made in another showing a dense lymphoid inlfi trate with atypical growth Hospital in January 2016, and she is free from lymphoma pattern and cells of large size (CD20+, CD79a+, CD5+, recurrence according to recent clinical and radiological Bcl2+, CD3-, CD30-, Bcl6-, Mum1-, Ki67 80%). A evaluations. new PET scan showed multiple pathological uptake of u fl orodeoxyglucose in inguinal regions and at the level of DISCUSSION the subcutaneous nodules, while the bone marrow biopsy did not show any inlfi tration. Consistent with the history The role of HCV in pathogenesis of NHL is well established. of two previous relapses and to the high expression of The regression of HCV-associated indolent lymphomas Bcl2, a histological reassessment was required on both after a successful AVT adds the demonstration that there the lymphoid tissue available at diagnosis and that from is a relationship between HCV and lymphomagenesis, the biopsy of the subcutaneous nodule. An analysis but there are no data about the response of DHL to with u fl orescence in situ hybridization for the detection AVTs. Because HCV is not integrated into the host of lymphoma-associated chromosomal abnormalities genome, there should be indirect mechanisms to induce was performed (Vysis LSI Bcl2 break apart probe, Vysis malignancy (“hit and run theory”). The main hypothesis LSI Myc break apart probe), showing additive copies of links the antigenic stimulation caused by CHC to the Bcl2 (18q21) in 82% and rearrangement of Myc in 89% chronic proliferation of B cells, to produce r fi stly a poly­ of the nuclei analyzed (8q24), respectively. Therefore, clonal and after a monoclonal expansion of these cells the n fi al diagnosis was that of DHL, a more aggressive resulting, in conjunction with further occurrence of [5] subtype of DBCL. In July 2015, the patient was firstly additional genetic mutations, in an overt NHL . Notably, prescribed a cycle of ifosfamide, etoposide, epirubicin several years have to pass in order to accumulate plus R (R-IEV regimen), followed by stem cell collection mutational changes, whereas a genetic predisposition or for a possible autologous stem cell transplantation; additional mutagenic effects in genes Bcl2, Bcl6 or Ccnd1 WJH|www.wjgnet.com 1247 October 18, 2016|Volume 8|Issue 29| Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma A B C H and E 25× H and E 400 × CD20 200 × D E F Ki67 200 × Bcl6 400 × Mum1 400 × Figure 4 Histological and immunohistochemical features of the diffuse large B cell lymphoma in the second relapse (cutaneous). A: In the cutaneous relapse a rather monomorphic lymphoid population was found; B: The rate of large lymphoid cells increased up to 100%; C: These large cells were B CD20+; D: The proliferation rate marked by Ki67 was around 95% in the blastic B cell population; E: The large B cells expressed poorly the germinal center marker Bcl6; F: Mum1 was found to be poorly expressed by the large B cells. DLBCL: Diffuse large B cell lymphoma; H and E: Hematoxylin and eosin; CD: Clusters of differentiation; Ki67: Cellular marker for proliferation; Bcl6: B Cell lymphoma 6; Mum1: Multiple myeloma oncogene 1. could explain the DHL mutation occurrence. Indeed, patients with HCV-related lymphoma, two DLBCL were HCV could induce a mutator phenotype, which involves successfully treated with sofosbuvir and daclatasvir (an enhanced mutations of many somatic genes. In the NS5A protease inhibitor), with complete hematological [13] management of HCV-related DLBCL, anthracycline-based response after 6 mo . There are no reported cases of chemotherapy, usually CHOP, associated with R (chimeric DHL and CHC treated by new DAAs. anti-CD20 monoclonal antibody) is the standard of According to clinical data, we could exclude an ad- [6] [7] care . Unlike indolent B-cell lymphomas , AVT does not vanced liver fibrosis in our patient and we estimated play a signic fi ant role in HCV ­positive DLBCL. Sequential a minimal risk of liver decompensation. Therefore, the immune-chemotherapy followed by ATV has been patient was firstly successfully treated with R-CHOP, used in two studies with promising results leading to but after the r fi st hematological relapse, a new immuno­ improved clinical outcome and prolonged disease free suppressive therapy with R-DHAP schedule caused an [8,9] survival . On the other hand, a French study reported overt liver failure. R has been described to enhance viral a higher overall survival and progression free survival in replication due to the immune system imbalance, but patients treated r fi stly by AVT, followed in some cases by the rate of severe hepatic complications remains low, [10] chemotherapy . All these studies are developed in the with some exceptions, such as in presence of hepatitis “IFN era”, both alone or in combination with RBV and, B virus or HIV infection, cirrhosis or hepatocellular car- [7,14] more recently, with protease inhibitors like telaprevir and cinoma . There are controversial studies about the boceprevir. An IFN-based immunomodulatory and anti- impairment of liver function, which could be caused both angiogenetic mechanism could be supposed, although by a toxicity of immune-chemotherapy treatment and by IFN-based AVTs cannot be started in most cases, HCV reactivation. Indeed, it is not clear if the anecdotal because of contraindications and heavy side effects. episodes of liver failure in this setting are due to higher A few reports demonstrated lymphoma regression HCV replication and enhanced necro-inflammatory [11] after HCV clearance with new DAAs. Rossotti et al activity, or to a direct chemo-toxicity. Chemotherapy- reported a rapid virological and hematological response induced HCV reactivation in DLBCL is rarely reported, [15-17] with the combination of a NS3/NS4A inhibitor (faldaprevir) whereas there are no data about HCV and DHL . and a non-nucleoside NS5B inhibitor (deleobuvir) in In our case the liver failure may have been caused by a patient with HCV associated splenic marginal zone an add-on effect of HCV reactivation and liver chemo- [12] lymphoma. In another report, Sultanik et al showed toxicity, as well suggested by a higher increase of complete regression of MZL after 12 wk of therapy with Gamma-Glutamyl Transpeptidase, marker of liver toxicity, sofosbuvir (an NS5B RNA-dependent RNA polymerase instead of a pure elevation of Alanine Aminotransferase, inhibitor) and RBV. In a case series from France of v fi e a possible expression of an inflammatory response WJH|www.wjgnet.com 1248 October 18, 2016|Volume 8|Issue 29| Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma HCV-mediated. Interestingly, during the liver failure Differential diagnosis Inflammatory process of the throat, metastatic cancer of head-neck sites, HCV-RNA slightly dropped, so we can suppose that lymphoproliferative disease. the event was caused by immune re-activation rather than by HCV direct effect on the necro-inflammatory Laboratory diagnosis activity. Following the second immune-chemotherapy All blood tests were within normal limits except for high HCV-viremia. and after recovering from the acute liver failure, the patient started antiviral therapy with second generation Imaging diagnosis DAAs: OBV/PTV/r and DSV. This multi-targeted 3-DAAs Computed tomography showed multiple lymph nodes on both sides of the regimen in combination with or without RBV is approved diaphragm. in many countries to treat HCV genotype 1-4 infection. Approval for the treatment of HCV genotype 1 patients Pathological diagnosis with compensated cirrhosis was based on the evidence Double-hit B cell lymphoma. of a phase 3 trial of 380 patients in which OBV/PTV/r and DSV plus RBV achieved SVR rates at post-treatment Treatments week 12 (SVR12) of 91.8% and 95.9% after 12 or 24 Chemotherapy, radiotherapy and antiviral therapy for HCV. [18] wk of therapy, respectively . In the past, the AVTs for HCV were conceived with IFN-based regimens, so an Related reports immunomodulatory effect due to interactions with both Double-hit B cell lymphoma is a rare entity with no standardized chemo- the adaptive and innate immune response of the host, therapeutic strategies and its association with HCV-infection is not ever been further than an anti-inflammatory and antiviral effect investigated. There are no reports about the efc fi acy of antiviral therapy for HCV plus chemotherapies, in order to cure this pathology in presence of HCV. by inhibiting the synthesis of various cytokines, were possibly responsible for the remission of HCV-related lymphomas. In this context, at the moment, there are no Terms explanation HCV could induce B cell proliferation and cause non-Hodgkin lymphoma. The den fi itive data about IFN free therapies, and it remains typical HCV-related lymphomas are marginal zone lymphoma and diffuse large to be solved whether IFN is crucial for its direct antitumor B cell lymphoma. Double-hit B cell (DHL) is a new kind of lymphoma with more and anti-proliferative effect against NHL further than for aggressive outcome, and it is characterized by chromosomal rearrangements, its antiviral effect. specifically of Myc oncogene and either B cell lymphoma 2 and B cell In conclusion, this is the r fi st case, to our knowledge, lymphoma 6 oncogenes or gene for Cyclin D1. of DHL and CHC successfully treated by new DAAs. According to our experience, DHL must be suspected Experiences and lessons in case of HCV-related lymphoma, and an early diag- DHL must be suspected in case of HCV-related lymphoma, and an early diagnosis could direct towards a different hematological management, because nosis could direct towards a different hematological a poor prognosis should be expected. A potential favorable effect of new antiviral management, because a poor prognosis should be therapies on DHL regression should be investigated. expected. Moreover, DAAs triple regimen with OBV/ PTV/r and DSV achieves a rapid virological response, Peer-review and the result is sustained during immunosuppressive This manuscript has reported the first case of DHL and CHC successfully therapy, without evidence of HCV reactivation. Finally, treated by new DAA. we can suggest that in cases of aggressive HCV-related lymphoma, it is mandatory to treat the HCV infection with the new IFN-free regimens at least after the first REFERENCES chemotherapy cycle. This choice could avoid a liver failure 1 Negri E, Little D, Boiocchi M, La Vecchia C, Franceschi S. B-cell in case of re-treatment with hepatotoxic drugs, and it non-Hodgkin’s lymphoma and hepatitis C virus infection: a syste- matic review. Int J Cancer 2004; 111: 1-8 [PMID: 15185336 DOI: allows a better and safer management of hematological 10.1002/ijc.20205] disease. A potential favorable effect of the AVTs on DHL 2 Pellicelli AM, Marignani M, Zoli V, Romano M, Morrone A, regression should be investigated. Nosotti L, Barbaro G, Picardi A, Gentilucci UV, Remotti D, D’ Ambrosio C, Furlan C, Mecenate F, Mazzoni E, Majolino I, Villani R, Andreoli A, Barbarini G. Hepatitis C virus-related B cell ACKNOWLEDGMENTS subtypes in non Hodgkin’s lymphoma. 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J Hepatol 2016; 64: 301-307 [PMID: HCV-associated disseminated marginal zone lymphoma under 26476290 DOI: 10.1016/j.jhep.2015.10.005] P- Reviewer: Einberg AP, El-Shabrawi MH, Ji FP S- Editor: Qiu S L- Editor: A E- Editor: Li D WJH|www.wjgnet.com 1250 October 18, 2016|Volume 8|Issue 29| Published by Baishideng Publishing Group Inc 8226 Regency Drive, Pleasanton, CA 94588, USA Telephone: +1-925-223-8242 Fax: +1-925-223-8243 E-mail: bpgoffice@wjgnet.com Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx http://www.wjgnet.com © 2016 Baishideng Publishing Group Inc. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png World Journal of Hepatology Pubmed Central

Hepatitis C and double-hit B cell lymphoma successfully treated by antiviral therapy

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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
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1948-5182
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1948-5182
DOI
10.4254/wjh.v8.i29.1244
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Abstract

Author contributions: All the authors contributed equally to the conception and design of the article. B cells lymphoma is one of the most challenging extra- hepatic manifestations of hepatitis C virus (HCV). Institutional review board statement: This case report Recently, a new kind of B-cell lymphoma, named double- was exempt from the Institutional Review Board standards at hit B (DHL), was characterized with an aggressive University of Campus Bio Medico of Rome. clinical course whereas a potential association with HCV was not investigated. The new antiviral direct agents Informed consent statement: The patient involved in this clinical case gave her written informed consent authorizing use (DAAs) against HCV are effective and curative in the and disclosure of her protected health information. majority of HCV infections. We report the first case, to our knowledge, of DHL and HCV-infection successfully Conflict-of-interest statement: All the authors have no treated by new DAAs. According to our experience, a DHL conflicts of interests to declare. must be suspected in case of HCV-related lymphoma, and an early diagnosis could direct towards a different Open-Access: This article is an open-access article which was hematological management because a worse prognosis selected by an in-house editor and fully peer-reviewed by external might be expected. A possible effect of DAAs on DHL reviewers. It is distributed in accordance with the Creative regression should be investigated, but eradicating HCV Commons Attribution Non Commercial (CC BY-NC 4.0) license, would avoid life-threatening reactivation of viral hepatitis which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on during pharmacological immunosuppression in onco- different terms, provided the original work is properly cited and haematological diseases. the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ Key words: Hepatitis C; Lymphoma; Direct antiviral agents; Double hit lymphoma; Chronic hepatitis C Manuscript source: Unsolicited manuscript © The Author(s) 2016. Published by Baishideng Publishing Correspondence to: Giovanni Galati, MD, Unit of Internal Group Inc. All rights reserved. Medicine and Hepatology, Department of Medicine, Università Campus Bio-Medico di Roma, via Álvaro del Portillo 21, 00128 Core tip: Rome, Italy. g.galati@unicampus.it B cells lymphoma is one of the most chall- WJH|www.wjgnet.com 1244 October 18, 2016|Volume 8|Issue 29| Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma enging extra-hepatic manifestations of hepatitis C other risk factors for hepatitis virus transmission. The virus. Recently, a new kind of B-cell lymphoma, named CHC was sustained by genotype 1b virus, with low necro- Double-hit B, was characterized with an aggressive inflammatory activity and mild liver fibrosis according clinical course. This is the first case described in literature to non-invasive evaluation performed by Fibroscan of double hit lymphoma with co-existing chronic (4.5 kPa), whereas HCV showed a high replication rate hepatitis C, successfully treated by new direct antiviral (4500000 UI/mL, Cobas AmpliPrep/Cobas TaqMan -Roche, therapies. This case suggests a potential favorable Rotkreuz, Switzerland). Ultrasound scans of the liver did effect of the new antiviral therapies on double hit not demonstrate signs of b fi rosis or spleen enlargement lymphoma regression. secondary to portal hypertension. Of interest, the patient reported a previous episode of major depression occurred in 2006 and, since then, she had been taking venlafazine Galati G, Rampa L, Vespasiani-Gentilucci U, Marino M, Pisani 75 mg/d. F, Cota C, Guidi A, Picardi A. Hepatitis C and double-hit B cell In July 2013, due to the enlargement of neck lymph lymphoma successfully treated by antiviral therapy. World J nodes, the patient underwent a hematological evaluation Hepatol 2016; 8(29): 1244-1250 Available from: URL: http:// and a lymph node biopsy, and she was n fi ally diagnosed www.wjgnet.com/1948-5182/full/v8/i29/1244.htm DOI: http:// with DLBCL (CD20+, CD30-, Bcl2+, Ki67 50%, Bcl6 + dx.doi.org/10.4254/wjh.v8.i29.1244 25%, negativity for CD10 and Mum1), with involvement of nodes on both sides of the diaphragm, bone marrow and spleen (Figure 1). Treatment with cyclophosphamide, doxorubicin, vincristine, prednisolone plus Rituximab INTRODUCTION (R) (R-CHOP regimen) plus prophylactic intrathecal Hepatitis C virus (HCV) is a major global public health injection of methotrexate and prednisone, was started. problem, although the newest and most effective In December 2013, i.e., after six courses of R-CHOP, antiviral therapies (AVTs), free from severe side effects the patient showed a complete remission of lymphoma related to interferon (IFN), are spreading in developed according both to Contrast Tomography plus Positron countries. This could lead in the next future to a lower Emission Tomography scans and to bone marrow biopsy. prevalence of chronic hepatitis C (CHC) and of its extra- Two additional doses of R were prescribed and, at that hepatic manifestations. Among these, the hematologic time, blood tests showed normal levels of transaminases, manifestations are the most challenging. Indeed, while HCV replication did not show any substantial HCV could induce B cell proliferation and cause mixed changes (Figure 2). In the following months, the patient [1] cryoglobulinaemia and non-Hodgkin lymphoma (NHL) . was referred to our Liver Unit and she was evaluated The typical HCV-related lymphomas are marginal zone for AVT. However, since “all-oral” AVTs for CHC was at lymphoma (MZL) and diffuse large B cell lymphoma that time unavailable in Italy, the patient was evaluated [2] (DLBCL) . The r fi st could benetfi from AVTs, whereas the for IFN-based AVT, but she presented relative and second group needs more aggressive chemotherapies absolute contraindications to IFN use, such as a previous and the only AVTs seem to be ineffective. More recently, episode of major depression, mild anemia, leucopenia a new kind of lymphoma named double-hit B cell (i.e., Haemoglobin 10.7 g/dL, White cells counts 1.980 (DHL) was described, characterized by chromosomal cells/mm ), as well as to ribavirin (RBV) use (anemia). rearrangements, specic fi ally of Myc oncogene and either We therefore asked our case to be evaluated for the B cell lymphoma 2 and B cell lymphoma 6 oncogenes expanded access program (EAP) which was ongoing [3,4] (Bcl2-Bcl6) or gene for Cyclin D1 (Ccnd1) . DHL with Paritaprevir (PTV), a NS3/4A protease inhibitor co- represents about 5% of all cases of DLBCL and affected formulated with NS5A inhibitor Ombitasvir (OBV) and patients generally have an aggressive clinical course the pharmacokinetic enhancer ritonavir (r), plus non- with poor prognosis, despite combination chemotherapy, nucleoside polymerase inhibitor Dasabuvir (DSV). Since with a median overall survival of less than 1-2 years. To lymphoma is a possible extra-hepatic manifestation of date, due to the limited literature concerning this type HCV, the pharmaceutical industry committee accepted of lymphoma, the specic fi treatment is still not clear. A our patient for participation to the EAP. Unfortunately, in potential correlation between HCV and DHL has never October 2014, the patient experienced the r fi st relapse of been investigated. lymphoma at the right maxillary sinus (Figure 3), whereas We describe the first case, to our knowledge, of a bilateral bone biopsies were negative. Since chemotherapy patient affected by DHL and CHC who underwent a was urgent, cisplatin, cytarabin, dexamethasone plus R successful antiviral treatment with IFN-free therapy (R-DHAP regimen) were started. After the second cycle (ombitasvir/paritaprevir/ritonavir and dasabuvir). of R-DHAP, liver tests worsened, with a rapid evolution to liver failure, i.e., jaundice and ascites (Figure 2). She was admitted to our Unit and the liver decompensation CASE REPORT was successfully treated with diuretics and anti-oxidant The patient was a 39-year-old Caucasian woman, who infusion (glutathione 2 g/d until recovery). tested HCV positive in 2013 during a routine medical From February 2015 to March 2015 she underwent evaluation. She had not history of blood transfusions or local radiotherapy on the right maxillary sinus (30 Gray). WJH|www.wjgnet.com 1245 October 18, 2016|Volume 8|Issue 29| Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma A B C H and E 200 × H and E 400 × CD20 400 × D E F Ki67 400 × Bcl6 400 × Mum1 400 × Figure 1 Histological and immunohistochemical features of the diffuse large B cell lymphoma at the primary diagnosis. A: In the lymph node a polymorphic lymphoid population is seen; B: Large lymphoid cells prevailed; C: These large cells were B CD20+; D: The proliferation rate marked by Ki67 was around 20% with respect to the overall population, but about 40% if compared with the blastic B cell population; E: The large B cells expressed mainly the germinal center marker Bcl6; F: Mum1 was not found expressed at the primary diagnosis. DLBCL: Diffuse large B cell lymphoma; H and E: Hematoxylin and eosin; CD: Clusters of differentiation; Ki67: Cellular marker for proliferation; Bcl6: B cell lymphoma 6; Mum1: Multiple myeloma oncogene 1. Liver Second First failure relapse relapse Diagnosis R-IEV R-CHOP R-DHAP R-IEVR RT R R R R Antiviral therapy 1 0 HCV-RNA (UI/mL) ALT (U/L) GGT (U/L) Figure 2 This figure shows the trends of gamma-glutamyl transpeptidase, alanine amino-transferase and hepatitis C viremia - RNA during chemo- therapies and antiviral therapy. R: Rituximab; R-CHOP: Cyclophosphamide, doxorubicin, vincristine, prednisolone plus Rituximab; R-DHAP: Cisplatin, cytarabin, dexamethasone plus Rituximab; R-IEV: Ifosfamide, etoposide, epirubicin plus Rituximab; GGT: Gamma-glutamyl transpeptidase; ALT: Alanine amino-transferase; HCV: Hepatitis C viremia. After the liver tests returned to normal levels, she started 12 wk (Figure 2). The HCV-RNA showed a fast drop the triple DAAs regimen in the EAP, for a duration of since after two weeks of AVT (42 UI/mL), while viremia WJH|www.wjgnet.com 1246 October 18, 2016|Volume 8|Issue 29| August 2013 November 2013 February 2014 May 2014 August 2014 November 2014 February 2015 May 2015 August 2015 Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma A B C H and E 200 × CD20 400 × H and E 400 × E F Bcl6 400 × Mum1 400 × Ki67 400 × Figure 3 Histological and immunohistochemical features of the diffuse large B cell lymphoma at the first relapse (mucosal). A: In the mucosal relapse a polymorphic lymphoid population was found; B: The rate of large lymphoid cells increased up to 80%; C: These large cells were B CD20+; D: The proliferation rate marked by Ki67 was around 50%-60% with respect to the blastic B cell population; E: The large B cells expressed the germinal center marker Bcl6 (about 50%-60%); F: Mum1 was found to be expressed now by about 70% of the cells. DLBCL: Diffuse large B cell lymphoma; H and E: Hematoxylin and eosin; CD: Clusters of differentiation; Ki67: Cellular marker for proliferation; Bcl6: B Cell lymphoma 6; Mum1: Multiple myeloma oncogene 1. became undetectable (limit of quantic fi ation according to subsequently, she underwent a second cycle of R/IEV/R our virological test was 15 UI/mL) after 8 wk of therapy, (regimen with an additive administration of R), which and persisted undetectable both at the end of AVT and was burdened by infective complications requiring hos- 24 wk after. However, in May 2015, i.e., after 4 wk from pitalization and prolonged antibiotic therapies. At the the end of AVT, the patient experienced a new relapse of last hepatological follow-up visit in November 2015, i.e., lymphoma (Figure 4). Due to the appearance of multiple 24 wk after the end of AVT, HCV-RNA was permanently cutaneous nodules on the middle third of the left arm, undetectable despite the immunosuppressive therapy. on the posterior region of the chest wall and on the right Afterwards, the patient was evaluated for an allogenic and left a fl nks, a biopsy of one of them was indicated, stem cells transplantation, which was made in another showing a dense lymphoid inlfi trate with atypical growth Hospital in January 2016, and she is free from lymphoma pattern and cells of large size (CD20+, CD79a+, CD5+, recurrence according to recent clinical and radiological Bcl2+, CD3-, CD30-, Bcl6-, Mum1-, Ki67 80%). A evaluations. new PET scan showed multiple pathological uptake of u fl orodeoxyglucose in inguinal regions and at the level of DISCUSSION the subcutaneous nodules, while the bone marrow biopsy did not show any inlfi tration. Consistent with the history The role of HCV in pathogenesis of NHL is well established. of two previous relapses and to the high expression of The regression of HCV-associated indolent lymphomas Bcl2, a histological reassessment was required on both after a successful AVT adds the demonstration that there the lymphoid tissue available at diagnosis and that from is a relationship between HCV and lymphomagenesis, the biopsy of the subcutaneous nodule. An analysis but there are no data about the response of DHL to with u fl orescence in situ hybridization for the detection AVTs. Because HCV is not integrated into the host of lymphoma-associated chromosomal abnormalities genome, there should be indirect mechanisms to induce was performed (Vysis LSI Bcl2 break apart probe, Vysis malignancy (“hit and run theory”). The main hypothesis LSI Myc break apart probe), showing additive copies of links the antigenic stimulation caused by CHC to the Bcl2 (18q21) in 82% and rearrangement of Myc in 89% chronic proliferation of B cells, to produce r fi stly a poly­ of the nuclei analyzed (8q24), respectively. Therefore, clonal and after a monoclonal expansion of these cells the n fi al diagnosis was that of DHL, a more aggressive resulting, in conjunction with further occurrence of [5] subtype of DBCL. In July 2015, the patient was firstly additional genetic mutations, in an overt NHL . Notably, prescribed a cycle of ifosfamide, etoposide, epirubicin several years have to pass in order to accumulate plus R (R-IEV regimen), followed by stem cell collection mutational changes, whereas a genetic predisposition or for a possible autologous stem cell transplantation; additional mutagenic effects in genes Bcl2, Bcl6 or Ccnd1 WJH|www.wjgnet.com 1247 October 18, 2016|Volume 8|Issue 29| Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma A B C H and E 25× H and E 400 × CD20 200 × D E F Ki67 200 × Bcl6 400 × Mum1 400 × Figure 4 Histological and immunohistochemical features of the diffuse large B cell lymphoma in the second relapse (cutaneous). A: In the cutaneous relapse a rather monomorphic lymphoid population was found; B: The rate of large lymphoid cells increased up to 100%; C: These large cells were B CD20+; D: The proliferation rate marked by Ki67 was around 95% in the blastic B cell population; E: The large B cells expressed poorly the germinal center marker Bcl6; F: Mum1 was found to be poorly expressed by the large B cells. DLBCL: Diffuse large B cell lymphoma; H and E: Hematoxylin and eosin; CD: Clusters of differentiation; Ki67: Cellular marker for proliferation; Bcl6: B Cell lymphoma 6; Mum1: Multiple myeloma oncogene 1. could explain the DHL mutation occurrence. Indeed, patients with HCV-related lymphoma, two DLBCL were HCV could induce a mutator phenotype, which involves successfully treated with sofosbuvir and daclatasvir (an enhanced mutations of many somatic genes. In the NS5A protease inhibitor), with complete hematological [13] management of HCV-related DLBCL, anthracycline-based response after 6 mo . There are no reported cases of chemotherapy, usually CHOP, associated with R (chimeric DHL and CHC treated by new DAAs. anti-CD20 monoclonal antibody) is the standard of According to clinical data, we could exclude an ad- [6] [7] care . Unlike indolent B-cell lymphomas , AVT does not vanced liver fibrosis in our patient and we estimated play a signic fi ant role in HCV ­positive DLBCL. Sequential a minimal risk of liver decompensation. Therefore, the immune-chemotherapy followed by ATV has been patient was firstly successfully treated with R-CHOP, used in two studies with promising results leading to but after the r fi st hematological relapse, a new immuno­ improved clinical outcome and prolonged disease free suppressive therapy with R-DHAP schedule caused an [8,9] survival . On the other hand, a French study reported overt liver failure. R has been described to enhance viral a higher overall survival and progression free survival in replication due to the immune system imbalance, but patients treated r fi stly by AVT, followed in some cases by the rate of severe hepatic complications remains low, [10] chemotherapy . All these studies are developed in the with some exceptions, such as in presence of hepatitis “IFN era”, both alone or in combination with RBV and, B virus or HIV infection, cirrhosis or hepatocellular car- [7,14] more recently, with protease inhibitors like telaprevir and cinoma . There are controversial studies about the boceprevir. An IFN-based immunomodulatory and anti- impairment of liver function, which could be caused both angiogenetic mechanism could be supposed, although by a toxicity of immune-chemotherapy treatment and by IFN-based AVTs cannot be started in most cases, HCV reactivation. Indeed, it is not clear if the anecdotal because of contraindications and heavy side effects. episodes of liver failure in this setting are due to higher A few reports demonstrated lymphoma regression HCV replication and enhanced necro-inflammatory [11] after HCV clearance with new DAAs. Rossotti et al activity, or to a direct chemo-toxicity. Chemotherapy- reported a rapid virological and hematological response induced HCV reactivation in DLBCL is rarely reported, [15-17] with the combination of a NS3/NS4A inhibitor (faldaprevir) whereas there are no data about HCV and DHL . and a non-nucleoside NS5B inhibitor (deleobuvir) in In our case the liver failure may have been caused by a patient with HCV associated splenic marginal zone an add-on effect of HCV reactivation and liver chemo- [12] lymphoma. In another report, Sultanik et al showed toxicity, as well suggested by a higher increase of complete regression of MZL after 12 wk of therapy with Gamma-Glutamyl Transpeptidase, marker of liver toxicity, sofosbuvir (an NS5B RNA-dependent RNA polymerase instead of a pure elevation of Alanine Aminotransferase, inhibitor) and RBV. In a case series from France of v fi e a possible expression of an inflammatory response WJH|www.wjgnet.com 1248 October 18, 2016|Volume 8|Issue 29| Galati G et al . IFN-free therapy in HCV-related double-hit lymphoma HCV-mediated. Interestingly, during the liver failure Differential diagnosis Inflammatory process of the throat, metastatic cancer of head-neck sites, HCV-RNA slightly dropped, so we can suppose that lymphoproliferative disease. the event was caused by immune re-activation rather than by HCV direct effect on the necro-inflammatory Laboratory diagnosis activity. Following the second immune-chemotherapy All blood tests were within normal limits except for high HCV-viremia. and after recovering from the acute liver failure, the patient started antiviral therapy with second generation Imaging diagnosis DAAs: OBV/PTV/r and DSV. This multi-targeted 3-DAAs Computed tomography showed multiple lymph nodes on both sides of the regimen in combination with or without RBV is approved diaphragm. in many countries to treat HCV genotype 1-4 infection. Approval for the treatment of HCV genotype 1 patients Pathological diagnosis with compensated cirrhosis was based on the evidence Double-hit B cell lymphoma. of a phase 3 trial of 380 patients in which OBV/PTV/r and DSV plus RBV achieved SVR rates at post-treatment Treatments week 12 (SVR12) of 91.8% and 95.9% after 12 or 24 Chemotherapy, radiotherapy and antiviral therapy for HCV. [18] wk of therapy, respectively . In the past, the AVTs for HCV were conceived with IFN-based regimens, so an Related reports immunomodulatory effect due to interactions with both Double-hit B cell lymphoma is a rare entity with no standardized chemo- the adaptive and innate immune response of the host, therapeutic strategies and its association with HCV-infection is not ever been further than an anti-inflammatory and antiviral effect investigated. There are no reports about the efc fi acy of antiviral therapy for HCV plus chemotherapies, in order to cure this pathology in presence of HCV. by inhibiting the synthesis of various cytokines, were possibly responsible for the remission of HCV-related lymphomas. In this context, at the moment, there are no Terms explanation HCV could induce B cell proliferation and cause non-Hodgkin lymphoma. The den fi itive data about IFN free therapies, and it remains typical HCV-related lymphomas are marginal zone lymphoma and diffuse large to be solved whether IFN is crucial for its direct antitumor B cell lymphoma. Double-hit B cell (DHL) is a new kind of lymphoma with more and anti-proliferative effect against NHL further than for aggressive outcome, and it is characterized by chromosomal rearrangements, its antiviral effect. specifically of Myc oncogene and either B cell lymphoma 2 and B cell In conclusion, this is the r fi st case, to our knowledge, lymphoma 6 oncogenes or gene for Cyclin D1. of DHL and CHC successfully treated by new DAAs. According to our experience, DHL must be suspected Experiences and lessons in case of HCV-related lymphoma, and an early diag- DHL must be suspected in case of HCV-related lymphoma, and an early diagnosis could direct towards a different hematological management, because nosis could direct towards a different hematological a poor prognosis should be expected. A potential favorable effect of new antiviral management, because a poor prognosis should be therapies on DHL regression should be investigated. expected. Moreover, DAAs triple regimen with OBV/ PTV/r and DSV achieves a rapid virological response, Peer-review and the result is sustained during immunosuppressive This manuscript has reported the first case of DHL and CHC successfully therapy, without evidence of HCV reactivation. 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J Hepatol 2016; 64: 301-307 [PMID: HCV-associated disseminated marginal zone lymphoma under 26476290 DOI: 10.1016/j.jhep.2015.10.005] P- Reviewer: Einberg AP, El-Shabrawi MH, Ji FP S- Editor: Qiu S L- Editor: A E- Editor: Li D WJH|www.wjgnet.com 1250 October 18, 2016|Volume 8|Issue 29| Published by Baishideng Publishing Group Inc 8226 Regency Drive, Pleasanton, CA 94588, USA Telephone: +1-925-223-8242 Fax: +1-925-223-8243 E-mail: bpgoffice@wjgnet.com Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx http://www.wjgnet.com © 2016 Baishideng Publishing Group Inc. All rights reserved.

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World Journal of HepatologyPubmed Central

Published: Oct 18, 2016

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